Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid.

Abstract

In the reward circuitry of the brain, α-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of Δ(9)-tetrahydrocannabinol (THC), marijuana's main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by reexposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of α7nAChRs. Despite a clear need, there are no medications approved for treatment of marijuana dependence. Modulation of KYNA offers a pharmacological strategy for achieving abstinence from marijuana and preventing relapse.

• Authors: Zuzana Justinova, Paola Mascia, Hui-Qiu Wu, Maria E Secci, Godfrey H Redhi, Leigh V Panlilio, Maria Scherma, Chanel Barnes, Alexandra Parashos, Tamara Zara, Walter Fratta, Marcello Solinas, Marco Pistis, Jack Bergman, Brian D Kangas, Sergi Ferré, Gianluigi Tanda, Robert Schwarcz, Steven R Goldberg
• Journal: Nature neuroscience (Nat Neurosci) Vol. 16 Issue 11 Pg. 1652-61 (Nov 2013) ISSN: 1546-1726 [Electronic] United States
• PMID: 24121737 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics
• Benzoxazines
• Cannabinoid Receptor Agonists
• Morpholines
• Naphthalenes
• Ro 61-8048
• Sulfonamides
• Thiazoles
• (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
• Dronabinol
• Kynurenic Acid

Topics

• Analgesics (administration & dosage)
• Animals
• Benzoxazines (administration & dosage)
• Brain (metabolism)
• Cannabinoid Receptor Agonists (pharmacology)
• Conditioning, Operant (drug effects)
• Cues
• Discrimination, Psychological (drug effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Dronabinol (pharmacology)
• Drug-Seeking Behavior (drug effects)
• Kynurenic Acid (metabolism)
• Male
• Memory, Short-Term (drug effects)
• Morpholines (administration & dosage)
• Naphthalenes (administration & dosage)
• Rats
• Rats, Long-Evans
• Rats, Sprague-Dawley
• Reinforcement, Psychology
• Saimiri
• Secondary Prevention
• Self Administration
• Substance-Related Disorders (drug therapy, metabolism, pathology)
• Sulfonamides (pharmacology)
• Thiazoles (pharmacology)
• Time Factors
• Wakefulness